OHSU

Martina Ralle, PhD

Cell Biology of Metals

 

My lab's research interests are centered on the regulatory role of metals in cellular biology. To approach this subject from a more universal perspective we are developing new tools to investigate and understand differences caused by changes in metal homeostasis in cells and/or tissues. We are specifically interested in exploring signaling pathways that lead to subcellular redistributions of metals as well as changes in redox pathways as a cellular response to insult. We are working at the interface of biochemistry, biology, and medicine using and developing a range of spectroscopic and biochemical techniques with the highest possible sensitivity under the most relevant physiological conditions. We are collaborating with clinicians and basic researchers here at OHSU as well as elsewhere in the US and Europe. My own expertise is centered around X-ray spectroscopic applications in biology as well as mass spectroscopy such as bulk elemental analysis (ICPMS, LC-ICPMS) and protein/peptide identification (proteomics, MS-MS).

Metal imaging

We have optimized an imaging technique based on synchrotron X-ray radiation (SXRF) quantitatively analyze elements in intact biological samples. The advantages of SXRF are its sensitivity (attomolar range (10-18)) and resolution (nanoscopic, subcellular) without the need of using dyes or any chemical alterations. It requires powerful X-ray sources that produce highly brilliant X-ray beams in a small focused spot which are available only at third generation synchrotron sources such as the Advanced Photon Source in Argonne, Il. In a typical SXRF experiment, samples are scanned over an x-y area and the fluorescence for multiple elements is detected simultaneously. The resulting 2-D images display the relative abundance of the elements within the measured area. To determine the oxidation state of a metal the X-ray microprobe is held stationary while the energy is scanned to obtain an X-ray absorption edge scan (µ-XANES). A major drawback to SXRF is that it is "blind" to organelle or cellular boundaries unless there are differences in elemental content. We are exploring the use of metal-tagged primary antibodies for SXRF as a reliable method to detect cellular and subcellular structures in tissues and cells.

The role of hepatic copper accumulation in Wilson disease

Wilson disease (WD) is a genetic disorder of copper metabolism associated with severe hepatic, neurological, and psychiatric abnormalities. A major hallmark of WD in patients is the accumulation of copper in the liver and frequently the brain. We are specifically interested in the distribution, concentration, and oxidation state of copper as a function of disease progression. We are further determining whether changes in intracellular copper levels cause changes in subcellular redox potentials. Here, we are focusing on the major redox buffer in mammalian cells: GSH/GSSG.

Metals in Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurological disorder associated with extracellular amyloid-β (Aβ) deposits, Aβ peptide oligomerization, intracellular neurofibrillary tangles (NFTs), synaptic toxicity, oxidative stress, and metal dyshomeostasis. We are working with Tg2576 mice or post-mortem human tissue in collaboration with Drs Quinn and Woltjer at OHSU to investigate metal concentrations, distributions and changes thereof in animal and human tissue.

 

Link to PubMed listing